~Osteoporosis, Part 2

~Osteoporosis, Part 2
Reprinted with permission of Life Extension®.

Vitamin/Minerals and Bone Loss

  • Vitamin K
  • Exercise
  • Bisphosphonates
  • Possible Mechanisms
  • Pros & Cons
  • Research

Calcium is the mineral that automatically comes to mind when considering osteoporosis treatment. However, although bone contains large amounts of calcium, other minerals need to be considered as important in the treatment and prevention of osteoporosis. For example, other trace minerals (minerals needed in small amounts for specific tasks--usually enzyme activation) would include zinc, magnesium, boron, and silicon.

Many people in North America who consume an average diet have magnesium deficiency, and magnesium is important in bone structure. Magnesium deficiency comes about because most magnesium in our diet comes from the magnesium contained in the chlorophyll molecule found mainly in dark green leafy vegetables--not something that most people eat on a daily basis. Magnesium intake should be about half that of calcium, approximately 300-500 mg a day. If not provided in the diet, then magnesium should be supplemented. Some researchers are now also reporting that magnesium deficiency plays a significant role in the development of osteoporosis (Dreosti 1995). Studies have shown that women with osteoporosis tend to have a lower magnesium intake than normal and lower levels of magnesium in their bones. Recommendations for postmenopausal women to increase calcium intake can lead to an unfavorable Ca to Mg ratio unless the magnesium intake is increased accordingly; the optimum ratio of Ca to Mg is believed to be 2:1. A magnesium deficiency can also affect the production of the biologically active form of vitamin D, thereby further promoting osteoporosis. Some research shows that magnesium supplementation is effective in treating osteoporosis. Magnesium supplementation (over and above the current recommended daily allowance) may suppress bone turnover in young adults and some researchers speculate that it may also help prevent age-related osteoporosis (Dimai et al. 1998).

Significant calcium imbalance can come about as a result of high intakes of phosphorus. Phosphorus is present in high quantities in protein-containing foods and soft drinks. There is some evidence that due to the large increase in soft drinks in the last decade that this factor alone may contribute to poor peak bone mass in younger individuals. Based on data from more than 4000 children aged 2-17 years, soda consumption among children and adolescents rose 41% in the time period of 1989-1991 compared to 1994-1995. This displaced milk and juice, which are the leading sources of many vitamins and minerals in the American diet (Wyshak 2000). A 1994 study of 127 children aged 8-16 found that 39% of the girls and 41% of the boys had a history of bone fracture. Girls who consumed greater amounts of cola beverages had a higher incidence of fractures than those who consumed low amounts. A high calcium intake was found to protect against fractures, particularly among girls who had high physical activity (Ballew et al. 2000).

Because other trace minerals have been implicated in osteoporosis, the following regimes are recommended for mineral supplementation:

  1. Obtain as much calcium and magnesium and other trace minerals from your diet as possible by drinking milk (if tolerated) and eating dark green leafy vegetables, broccoli, nuts, and seeds; eliminate or reduce the use of colas and other soft drinks in order to decrease phosphorus intake. Postmenopausal women should probably supplement with calcium/magnesium capsules. Calcium citrate is generally better absorbed and utilized than calcium carbonate. Calcium bis-glycinate absorbs even better than calcium citrate. Daily intakes should reach at least 1000 mg of calcium and 500 mg of magnesium, along with sufficient trace minerals including zinc, boron, and copper.
  2. For bone mineral maintenance and replacement, the Life Extension Foundation recommends that women take between 1000-2000 mg of elemental calcium along with 600-1000 mg of elemental magnesium every day. The addition of between 400-1000 IU of vitamin D3 is mandatory to ensure optimal calcium absorption. The inability to absorb calcium is a major reason that calcium therapy fails to prevent or slow the progression of osteoporosis. Vitamin D3 taken with calcium will normally promote absorption and assimilation of calcium into the bone matrix. Vitamin D3 has also been shown to promote the production of IGF-I and other growth factors in osteoporotic patients, which improves osteoblast (bone-building) function. Other minerals that are important for healthy bone metabolism include at least 30 mg a day of elemental zinc, 3 mg a day of elemental manganese, and 2 mg of elemental boron a day.
  3. There are dietary supplements designed to prevent and treat osteoporosis. (Bone Health) It is best to take calcium supplements with meals. Although certain fibers, such as wheat bran, psyllium, guar gum, and pectin, can interfere with mineral absorption, calcium absorbs better with meals. The recommended time to take the supplement would be at bedtime.

Vitamin K

One of the most scrutinized groups ever is the 85,000 female nurses who took part in the Nurses' Health Study. Researchers have been tracking the eating habits and health histories of these women since 1980. One of the things they've looked at is which participants were more likely to break a bone. Fractures are the classic symptom of osteoporosis.

Because eating animal protein has been linked to osteoporosis, an analysis was undertaken to determine whether meat-eating had an adverse effect on the nurses' bone density. In 1996, researchers reported the results. Nurses who ate 3 oz of meat or more per day had a significantly increased risk of forearm fracture compared to those who ate less than 2 oz (Feskanich et al. 1996).

Diets with more vegetables and less meat are higher in vitamin K. Another group of researchers wanted to know if there is a relationship between vitamin K intake and hip fracture in the same nurses. Using 10 years of data on 72,000 participants, Feskanich et al. (1999) came to the conclusion that the nurses who received the most vitamin K were about a third less likely to get a hip fracture. Those who ate lettuce every day slashed their risk of hip fracture in half compared to those who ate it once a day or less (lettuce is a source of vitamin K) (Feskanich et al. 1999). The significance of taking vitamin K was greater than taking synthetic estrogen, which did not protect the nurses' bone density in this study, nor did vitamin D. In fact, women who took a lot of vitamin D, but had low intakes of vitamin K, had a doubled risk of hip fracture! Although vitamin D increases the amount of bone-friendly osteocalcin, only vitamin K can make it work properly.

Most osteoporosis studies are done on postmenopausal women because this group experiences a dramatic decline of bone density. Vitamin K shows remarkable results against bone loss in this population. In a study from The Netherlands, 1 mg of vitamin K a day for 2 weeks increased a bone building protein gamma-carboxyglutamic acid (Gla) in postmenopausal women, helping to elevate it (Knapen et al. 1989). Another study shows that vitamin K slows calcium loss by one-third in people who have a tendency to lose it (Knapen et al. 1993). Drugs containing vitamins K1 and K2 are being used to treat osteoporosis (Hodges et al. 1991). The doses used in Japan are 45 mg a day (Shiraki et al. 2000).

In the last 10 years, vitamin K has been established to play a significant role in human health including the metabolism of bone. Human intervention studies show it can reduce fracture rate and can increase bone mineral density in osteoporotic individuals. Also, there has been shown to be a synergism between vitamin K1, especially when coadministered with vitamin D. Several mechanisms have been suggested about how vitamin K affects bone metabolism. Besides the effect on the protein involved in bone mineralization, there is also increasing evidence that it positively affects calcium balance, which plays a role in bone metabolism (Craciun et al. 1998). The Institute of Medicine in 2001 increased the dietary reference intake (DRI) of vitamin K by about 50% to 90 mcg/day for females and 120 mcg/day for males (Weber 2001). For prevention, the suggested dose is a vitamin K supplement that provides 9 mg of K1 and 1 mg of K2, that is, 10 mg of vitamin K a day. To treat osteoporosis, doses up to 45 mg a day of vitamin K1/K2 should be used only if a physician monitors blood coagulation factors to make sure that the vitamin K is not causing blood to overcoagulate.

The Importance of Exercise

Exercise is an effective therapy for preventing and treating osteoporosis. Its importance cannot be overstated. A study was performed to evaluate the effectiveness of certain exercises for the treatment of postmenopausal osteoporosis. Both back extension and posture exercises lasting for 1 hour were undertaken twice a week, as well as fast walking exercises 3 times a week for 1 hour. At the end of the study, women who added exercise to their medical therapy increased spinal bone density by 4.4%, while women receiving only bone-restoring medicines showed an increase in spinal bone density of just 1.6% (Belenoglu et al. 1997).

Treatment of Osteoporosis with Bisphosphonates

Another class of agents used to treat osteoporosis are bisphosphonates, which are essentially bone-rebuilding drugs. These include: alendronate (Fosamax), tiludronate (Skelid), pamidronate (Aredia), etidronate (Didronel), risedronate (Actonel), and zoledronic acid (Zometa). Bisphosphonates work primarily by decreasing calcium resorption (bone breakdown). The net result is an increase in bone mineral density (BMD) and a reduced risk of fractures (Greenspan et al. 2000; Fleisch 1997). German researchers, who reviewed a number of studies, concluded that, "From systematic research the best external evidence is available for a supplementation with calcium and vitamin D and a therapy with the bisphosphonates alendronate or risedronate, as well as the selective estrogen receptor modulator raloxifene (Evista)"(Minne et al. 2002).

To date, many studies have shown that bisphosphonates are effective for treating osteoporosis and preventing it in high-risk groups, particularly postmenopausal women. At the University of Heidelberg, Germany, bisphosphonates have been shown to prevent vertebral fractures in osteoporotic patients and reduce the incidence of new fractures of the femoral neck in those with preexisting fractures. The authors write that, "The introduction of bisphosphonates into the treatment of osteoporosis is definitely an enrichment of the therapeutic spectrum in conjunction with the basic treatment comprising calcium, vitamin D, diet, and physical measures" (Wuster et al. 1997).

The two bisphosphonates, etidronate and alendronate, for example, have been proven to increase bone mass and decrease fracture incidence at the spine, hip, and other sites by 50% compared to control rates in postmenopausal women (Russell et al. 1999). Meanwhile, researchers in New Zealand reported similar results following a 2-year randomized, double-blind, placebo-controlled study of pamidronate (150 mg a day) in 48 postmenopausal women with osteoporosis. Findings showed that the bone mineral density, which was measured at 6-month intervals, revealed a progressive increase in the entire body at all skeletal sites, although no significant changes occurred in the placebo group. There were nearly twice as many fractures per year occurring in the placebo group (24 per 100) than in the pamidronate group (13 per 100) (Reid et al. 1994). Also, a South American study found that 100 mg daily of oral pamidronate in postmenopausal women with confirmed osteoporosis resulted in a lowered rate of height loss and significantly lower incidence of total number of new fractures and new hip fractures (Man et al. 1997).
Table 1: Bisphosphonate Drugs

NameGeneric NameDosage
Fosamax*Alendronate10mg a day or 70mg a week
Actonel*Risedronate5mg a day
ArediaPamidronate (IV injection)30-90mg a month
ZometaIbandronate and Zolendronic acid (IV injectipj)4mg a year
SkelidTiludronate400mg a day
DidronelEtidronate5mg a day

The bisphosphonate drugs listed above have a narrow range of safety and must be prescribed by a knowledgeable physician.

*Actonel and Fosamax are the only bisphosphonate drugs that are presently approved in the United States for the treatment of osteoporosis.
In larger experiments, such as the Vertebral Efficacy with Risedronate Therapy (VERT) study, investigators looked at 2458 women under 85 with postmenopausal osteoporosis and at least one vertebral fracture. Subjects were randomly assigned to oral risedronate 2.5 or 5 mg a day or placebo for 3 years. All received 1000 mg calcium a day, and those with low vitamin D levels received up to 500 IU a day. The 3-year, 5-mg treatment decreased the cumulative incidence of new vertebral fractures by 41% and invertebral fractures by 39%. Bone mineral density increased significantly, compared with placebo, at the lumbar spine (5.4% versus 1.1%), femoral neck (1.6% versus 1.2%) and at other measured sites (Harris et al. 1999).

The most definitive data regarding postmenopausal women comes from the United States-based Fracture Intervention Trial (FIT), the largest osteoporosis clinical trial to date involving more than 6000 women aged 54-81. Researchers examined the effect of daily alendronate in 2027 women with vertebral compression fractures over a 3-year period and in 4432 without fractures over a 4-year period. In the group with existing fractures, they found that alendronate increased bone mineral density by 8% at the spine and 5% at the hip, while decreasing the incidence of all clinical fractures from 18.2% in placebo to 13.6% in the treated group, and vertebral compressions decreased from 15% to 8% (Black et al. 1996). However, differences were not significant between the test and placebo group in the branch of the study looking at women without baseline fractures (Cummings et al. 1998). All participants reporting calcium intakes of 1000 mg a day or less received a supplement containing 500 mg of calcium and 250 IU of vitamin D. Subjects were randomly assigned to either placebo or 5 mg a day of alendronate sodium for 2 years, changing to 10 mg a day for the remainder of the trial. Results showed that alendronate increased bone mineral density at all sites studied and reduced clinical fractures from 312 in the placebo group to 272 in the intervention group, although not significantly (14%).

Studies have also demonstrated that bisphosphonates are effective for osteoporosis resulting from secondary or unknown causes. For example, in cancer patients, bisphosphonates are standard treatment for hypercalcemia of malignancy (HCM), a skeletal complication that affects more than 10% of all cancer patients, and 20-40% of advanced cancer cases. It is especially common in patients with bone metastases, and those with breast and prostate cancer account for about 80% of bone metastases. Overstimulated osteoclasts result in an increased rate of bone resorption, causing bone weakening, while excess calcium makes its way into the bloodstream and creates complications, such as dehydration, fatigue, nausea, vomiting, confusion, and coma (Diel et al. 2000).

In a Belgian study, researchers gave 26 patients with either age-related or glucocorticoid-induced osteoporosis 60 mg of pamidronate intravenously every 3 months for 1 year. Researchers found that after only 3 months of treatment, patients' pain scores, due to chronic back pain from osteoporotic vertebral fractures, fell from 3.2 to 1.2 in both osteoporotic groups (Gangji et al. 1999). Meanwhile, Australian researchers suggest that, based on medical literature, postmenopausal women receiving corticosteroids should be given bisphosphonates, vitamin D metabolite, or hormone replacement (in that order) to prevent or reverse associated bone loss (Sambrook 2002).

In Denmark, researchers examined the effect of 10 mg daily of alendronate on lumbar spine bone mineral density in 32 patients with low bone mineral density, due to complications from Crohn's disease, for 12 months. Bone density increased by 4.6% in the lumbar spine and 3.3% in the hip in the alendronate group, respectively, compared to a decrease of 0.9% and 0.7% at the same sites in the placebo group. Authors concluded that 10 mg daily of alendronate increased bone mineral density in patients with Crohn's disease and was safe and well tolerated (Haderslev et al. 2000).

Likewise, in liver disease and liver transplant patients, for whom osteoporosis is a common complication, giving intravenous bisphosphonates (pamidronate) preoperatively prevented fractures in high-risk patients. Patients were treated with pamidronate every 3 months, before surgery and for 9 months afterward and were compared to an untreated group. None of those receiving bisphosphonate therapy (0 out of 13) suffered postoperative fracture, whereas 31% of those who went untreated did (Reeves et al. 1998).

Possible Mechanisms

Researchers know that bisphosphonates have an incredible affinity for bone, binding to calcium and building up in the mineralized bone matrix, so that it is more resistant to breakdown by osteoclasts. Still, it is not perfectly clear how they work. It is suspected that bisphosphonates affect signaling between osteoblasts and osteoclasts. Some in vitro studies have suggested that bisphosphonates may initiate macrophage death, thereby also overcoming their deleterious effects on osteoblasts. Macrophages are found on osteoblasts and are thought to have some responsibility for excessive bone resorption, namely by impeding the activity and survival of osteoblasts. Researchers found that adding bisphosphonates to cocultures of osteoblasts and macrophages blocked the adverse effects of macrophages on osteoblasts. Bisphosphonates increased the number of osteoblasts by 82% and reduced the number of macrophages. Also, control cocultures revealed fewer osteoblasts than the treated ones (Evans 2002).

Because of various modes of action observed in studies, bisphosphonates have been classified into two groups. Bisphosphonates that closely resemble pyrophosphate--a normal byproduct of human metabolism (such as clodronate and etidronate)--are incorporated into adenosine triphosphate (ATP) analogues, which create compounds that are believed to build up and lead to osteoclast death (Martin et al. 2000). The newest generation of bisphosphonates, which contain nitrogen (such as pamidronate, alendronate, risedronate, and ibandronate), are believed to inhibit protein prenylation (post-translational modification) within the mevalonate pathway. The mevalonate pathway is responsible for the biosynthesis of cholesterol, other sterols, and isoprenoid lipids. Isoprenoid lipids are key in the prenylation of intracellular signaling proteins (GTPases) that, when activated, regulate a number of processes, including osteoclast activity. It is believed that by impeding the function of these regulatory proteins, bisphosphonates result in blocking osteoclast functioning and causing apoptosis (Wuster et al. 1997).

Weighing Pros & Cons

Besides attempting to unravel how bisphosphonates work, researchers are also aiming to address their benefits and risks. The fact that bisphosphonates bind so strongly to bone and confine their activity to the skeleton has made clinicians confident about their safety profile. The positive aspect of bisphosphonates is that, because their effects are limited to bones, adverse effects elsewhere in other body tissues and organs are minimal (Fleisch 1997). However, thanks to their antiresorptive properties, bisphosphonates have been accused of substantially reducing bone turnover, in turn, impairing microdamage repair and causing increased bone mineralization, which can increase bone fragility. Thus, it is important to weigh how "osteoporosis therapies may also affect bone architecture by causing the redistribution of bone structure. Restructuring of bone during treatment may change bone fragility, even in the absence of drug effects on bone mineral density (BMD)" (Thiebaud et al. 1994).

Bisphosphonates also have some side effects, regardless of their narrow target of action. The most commonly reported side effects of oral bisphosphonates are gastrointestinal complications, such as esophagitis, gastritis, and diarrhea (Turner 2002). Intravenous delivery of bisphosphonates is being examined as a way to sidestep gastrointestinal adverse effects for those who cannot tolerate oral bisphosphonates, as well as a strategy to reduce dosing frequency significantly. There are adverse effects related to IV administration too, such as iritis (inflammatory eye disorder), muscle aches, and fever (Greenspan et al. 2000).

More Research

Studies are attempting to elucidate how bisphosphonates work best, the question focusing on delivery modes (oral versus IV), dosing amount and frequency. While some research has looked at intermittent dosing, given every few weeks or months, the latest findings reported in the New England Journal of Medicine suggest that just one annual injection of the bisphosphonate, Zometa (zoledronic acid), boosts bone mineral density as well as more frequently dosed oral bisphosphonates (Reid et al. 2002). In the study led by a New Zealand team of scientists, 351 postmenopausal women with low bone mineral density were randomized into five different treatment regimen groups: 0.25 mg, 0.5 mg, or 1 mg given every 3 months; a 2-mg dose every 6 months; a single 4-mg dose; or an inactive placebo. Increases in bone mineral density were reported among all Zometa-treated patients, which were comparable to increases associated with a daily regimen of any of the three oral bisphosphonates: Actonel, Fosamax, and Aredia. Larger studies with a 5-mg dose of Zometa are underway, one involving over 8000 men and postmenopausal women with osteoporosis, while another includes about 3000 men and postmenopausal women.

Another question being investigated is whether bisphosphonates are preferable to other treatments for the purpose of preventive therapy in high-risk groups. Some studies have debated whether bisphosphonate therapy is appropriate for patients under 60 with osteopenia (low bone density) without fractures. Generally, bisphosphonates have been indicated for individuals who have established osteoporosis or who are at high risk of the disease. A large British study called the Early Postmenopausal Intervention Cohort Study Group weighed bisphophonates against hormone replacement therapy (HRT). Investigators looked at the effect of 2.5 mg versus 5 mg of alendronate a day or placebo on bone mineral density in 1174 postmenopausal women under the age of 60. Also, 435 more women were randomized to receive alendronate, a placebo, or combination estrogen-progestin therapy. Results showed that controls lost bone mineral density at all measured sites. Contrarily, women receiving 5 mg of alendronate daily had an average increase in bone mineral density of 3.5% at the lumbar spine, 1.9% at the hip, and 0.7% for the total body. Women treated with 2.5 mg of alendronate daily had smaller increases in bone mineral density. And the estrogen-progestin combination showed a 1-2% better response rate than a 5-mg dose of alendronate (Hosking et al. 1998). While the study's authors concluded that bisphosphonates were comparable to hormone replacement therapy, others argue that HRT is still the best mode of preventive therapy in postmenopausal women because of additional beneficial effects on other organ systems, and not just bones (Ravn 2002).

Finally, researchers are still delving further into the question of how appropriate bisphosphonates are for treating osteoporosis in men, as the majority of studies have focused on women. It remains to be seen whether they work as well in men as they do in women, although clinical experience would suggest that is the case. Also, some research now indicates that bisphosphonates positively affect bone mineral density in men with idiopathic or secondary osteoporosis (American Society for Bone and Mineral Research 1998; Heilberg et al. 1998). Preliminary data from a large placebo-controlled trial of alendronate in men with osteoporosis also suggests a positive effect on bone mineral density (Anderson et al. 1997).

Continued . . .

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